Inflammation, as one of extremely common diseases, severely threatens human health and even brings great impacts on people's living quality. Taking arthritis which is one of the most common chronic diseases as example, it is estimated that there are a total of more than one hundred types, of which osteoarthritis and rheumatoid arthritis are the most common. There are about 355 million people suffering from a variety of joint diseases around the world, of which about 190 million people are osteoarthritis patients and more than 16.5 million people are rheumatoid arthritis patients. It is estimated that there are more than 100 million arthritis patients in China and this number is increasing every year. Although there are already anti-inflammatory and analgesic drugs (belonging to COX-2 inhibitors) available on the market, it is still unable to meet the increasing needs of clinical patients. Accordingly, the research and development of anti-inflammatory and analgesic drugs is still an important direction of drug development.
The traditional nonsteroidal anti-inflammatory drugs (traditional NSAIDs or non-selective NSAIDs) serve as the main anti-inflammatory and analgesic drugs for treating arthritis, including Ibuprofen, Diclofenac sodium, Meloxicam, Nabumetone, Naproxen, etc. Such drugs, on one hand, have anti-inflammatory and analgesic effects, and on the other hand, lead to a variety of severe gastrointestinal adverse reactions complications, for example, epigastric distress, ulcer, gastrointestinal bleeding, perforation and intestinal obstruction and etc. An estimated 60%-80% of such severe gastrointestinal complications have no signal of outbreak. It is speculated by some scholars that, possibly because masking the progress of ulcer by the analgesic effects of such drugs causes the chronic blood loss unconsciously, resulting in aggravation even massive hemorrhage without warning, making it too difficult to prevent or control. It is an unfortunate fact that, in America, about 16,500 people, as high as the number of those died of AIDS, died of gastrointestinal bleeding caused by such traditional nonsteroidal anti-inflammatory drugs in 1997, increasing the medical burden on society and family. Therefore, while remaining the excellent anti-inflammation and analgesic effects, developing anti-inflammatory and analgesic drugs capable of decreasing the incidences of severe adverse reactions becomes one of the issues concerned by the medical profession around the world.
The history of nonsteroidal anti-inflammatory drugs (NSAIDs) is a struggle against pain. Specifically, in 1899, the Bayer Company in Germany marketed a variant, acetylsalicylic acid, under the name of aspirin which is the prototype of NSAIDs. Aspirin marked the beginning of the modern anti-inflammatory treatment era, and over the next half-century, served as the main drug for anti-inflammatory treatment. Thereafter, NSAIDs of many types and structures had been successfully developed and marketed. Pyrazolone drugs, appeared in the 1950s, have excellent anti-inflammatory and analgesic effects, but deleterious effects on the bone marrow and other systems. One of indole acetic acid drugs (Indometacin), appeared in the 1960s, had been replaced by Sulindac and Acemetacin marketed in 1980s, due to its severe adverse reactions on gastrointestinal tract, liver and kidney and thus inapplicability to the old and patients suffering from liver, kidney and cardiovascular complications, in spite of excellent anti-inflammatory, analgesic and antipyretic effects. In 1970s, propionic acid drugs for example Ibuprofen, phenylacetic acid drugs for example Diclofenac Sodium, Oxicams for example Proxicam, Anthranilic acid drugs for example Etofenamate appeared. In 1980s, Naproxen was also one of the products marketed. In 1990s, cyclooxygenase-2 (COX-2) selective inhibitors were developed. NSAIDs, which can selectively inhibit the COX-1 and COX-2 enzyme activity, become the mainstream of research and development of anti-inflammatory and analgesic drugs.
Cyclooxygenases (COXs) are primary targets of the nonsteroidal anti-inflammatory drugs (NSAIDs). COXs function as catalytic synthesizing the intermediates, i.e., endoperoxides. (PGG2 and PGH2), of bioactive media such as prostaglandins (PGs) and thromboxane A2 (TXA2). In recent years, it has been found that COXs have two isomers, i.e., COX-1 and COX-2. These two isomers are 60% homologous, but different in both cellular distribution of tissues and biologic functions. PGE2 and PGI2 catalytically synthesized by COX-1 existing in normal tissues have cellular stabilization and protection functions. For example, in the gastric mucosa, PGE2 may promote the secretion of gastric mucus and protect the gastric mucosa. Gastric mucosa damage will be caused in the case of inhibited PGE2 biosynthesis or hyposecretion. COX-2 is cytokine-induced and just exists in the damaged tissues. Prostaglandins catalytically synthesized by COX-2 are inflammatory with high capability of Inducing inflammation and pain. The selective inhibition of COX-2 reduces the prostaglandins synthesized, so that the anti-inflammatory and analgesic effects are realized. As can be seen, the selective inhibition of COX-2 achieves not only the anti-inflammatory and analgesic purposes and also the reduced toxic or side effects to the gastrointestinal tract and kidney. Therefore, seeking COX-2 selective inhibitors is a major direction for the research and development of a new generation of NSAIDs. The fundamental research of COX-2 and the clinical application and safety assessment of COX-2 selective inhibitors become the common concerns of many subjects.
Cyclooxygenase (COX) protein was once believed to be produced by a single gene. COX is fundamentally composed of three independently folded units, i.e., epidermal growth factor domain, membrane binding domain and enzymatic activity domain. In 1990, the second isoenzyme of COX, which is different from the “typical” COX in both structure and function, was found in various cells. Hence, the typical COX as constitutive enzyme was named as COX-1 and the other COX as inducible enzyme was named as COX-2. The protein of COX-2 is made up of 604 amino acids. According to the well known crystal structure of COX, by the sequencing of COX-2, the difference in active sites between COX-2 and COX-1 is determined. The 523rd amino acid of COX-2 is valine, the structure of which is smaller than the leucine in a corresponding site of COX-1. Another difference lies in that there is a small recess which is produced in a different position on the 384th side-chain of leucine between COX-1 and COX-2. This difference exists because there are large non-steroidal anti-inflammatory drugs (NSAIDS) binding sites, so that the inhibition dedicated to COX-2 from the substrate is realized by enhancing the affinity with respect to the occupation of the macromolecule substrate. The discovery of COX-2 provides important theoretic basis for the development and use of the COX-2 selective inhibitors.
Most scholars believe that the pharmacological effects and adverse reactions of NSAIDs depend on the level of inhibition to COX-1 and COX-2. Specifically, the level of inhibition to COX-1 is higher, the adverse reactions on the digestive tract, kidney and etc. are severer; and, the level of inhibition to COX-2 is higher, the anti-inflammatory and analgesic effects are greater. Coxibs NSAIDs (COX-2 selective inhibitors) represented by Celecoxib, Rofecoxib and Valdecoxib are emerged in this context, with less adverse reactions on the gastrointestinal tract as their major advantage. It is generally recognized that COX-2 selective inhibitors have less adverse reactions on the gastrointestinal tract and less toxicity to the kidney than common non-steroidal anti-inflammatory drugs as they do not work on COX-1 and have no impact on the synthesis of PGI2 which may protect the gastrointestinal tract and the kidney. The COX-2 selective inhibitors, for example, Celecoxib, have an efficacy on chronic inflammation approximating to NSAIDs. However, they have quick analgesic effects slightly weaker when compared with ibuprofen and will cause a high incidence of cardiovascular side-effects. Over time, more adverse reactions have been further recognized, including: the recognition of adverse cardiovascular events caused as the COX-2 selective inhibitors have no inhibition to COX-1 and thromboxane A2 (TXA2) on the platelets.
A consensus has been reached on the clinical research of the COX-2 inhibitors. Specifically, due to different chemical structures, drugs even of the type may be completely different in safety; and some COX-2 inhibitors may even have cardiovascular protection function. The most important is that COX-2 selective inhibitors can produce more benefits than the traditional non-steroidal anti-inflammatory drugs, particularly in the reduction of gastrointestinal side effects. Hence, the search and development of anti-inflammatory and analgesic drugs still focus on COX-2 selective inhibitors.
Benzopyran compounds themselves, as novel COX-2 selective inhibitors, have carboxyl groups which will not be reacted with the hydrophobic groups in the active sites of COX-2. Benzopyran drug candidates, differentiated from diarylheterocyclicoxib compounds, have the same efficacy and selectivity as the diarylheterocyclicoxib compounds and show the capability to reduce the tactile allodynia in the rat model of neuropathic pain. It has been proved that benzopyran compounds have better treatment effects on inflammation and pain than the existing coxib compounds, and such compounds have a potential kidney protection function, thereby reducing the possibility of hypertension caused by the internal structure and the pharmacological and physiological properties. Hence, the development of such COX-2 selective inhibitors as anti-inflammatory and analgesic drugs is of great significance.